> Table of Contents > Prostate Cancer
Prostate Cancer
Jason K. Frankel, MD
Gregory Murphy, MD
Joseph R. Wagner, MD
image BASICS
DESCRIPTION
  • The prostate is a male reproductive organ that contributes seminal fluid to the ejaculate.
  • The prostate gland is about the size of a walnut, averaging 20 to 25 g in volume in an adult male; tends to enlarge after age 50
  • Three distinct zones delineate the functional anatomy of the prostate: peripheral zone (largest, neighbors rectal wall, palpable on DRE, most common location for prostate cancer), central zone (contains the ejaculatory ducts), and transition zone (located centrally, adjacent to the urethra).
  • Prostatic epitheilial cells produce prostate specific antigen (PSA), which is used as a tumor marker and in screening.
EPIDEMIOLOGY
Incidence
According to the National Cancer Institute, an estimated 220,800 men in the United States will be newly diagnosed with carcinoma of the prostate (CaP) in 2015.
Prevalence
  • About 2.8 million men are living with CaP in the United States
  • ˜27,540 men in the United States will die of CaP in 2015.
  • Mean age at diagnosis is 66 years.
  • Prostate cancer is the most commonly diagnosed nonskin cancer in men in the United States (˜15.9% lifetime risk) and second leading cause of cancer death in men (only ˜3% of all CaP results in CaP-related death).
  • Autopsy studies find foci of latent CaP in 50% of men in their 8th decade of life.
  • Probability of clinical CaP 10.9% (1 in 9) in men aged ≥70 years
ETIOLOGY AND PATHOPHYSIOLOGY
  • Adenocarcinoma: >95%; nonadenocarcinoma: <5% (most common transitional cell carcinoma)
  • Cells generally stain positive for PSA and prostatic acid phosphatase (PAP)
  • Location of CaP: 70% peripheral zone, 20% transitional zone, 5-10% central zone
Genetics
Elevated risk if first-degree relative diagnosed with CaP suggesting genetic component. Specifics unclear
RISK FACTORS
  • Age >50 years
  • African American race
  • Positive family history
  • Poorly understood environmental factors
GENERAL PREVENTION
There are no FDA approved drugs or diet modifications to prevent CaP.
  • Finasteride has been studied for this purpose. A moderate risk reduction associated with an increased risk of high-grade disease was encountered. Therefore, it has not been FDA approved for prevention (1)[A].
  • U.S. Preventive Services Task Force (USPSTF) recommends against PSA-based screen for prostate cancer, concluding the harm of screening outweighs benefit (2)[A].
  • For men ages 55 to 69 years, the AUA panel recommends shared decision making between physician and patient regarding PSA screening.
  • PSA screening is not recommended in patients with <10 years of estimated life expectancy.
image DIAGNOSIS
PHYSICAL EXAM
  • DRE to assess for prostatic masses, firmness, or asymmetry
  • Evaluate lumbar spine and lymph nodes for evidence of metastasis.
DIFFERENTIAL DIAGNOSIS
Benign prostatic hyperplasia, prostatitis, prostatic intraepithelial neoplasia (PIN), prostate stones, atypical small acinar proliferation (ASAP)
  • The high predictive value of ASAP for subsequent adenocarcinoma warrants repeat biopsy within 3 months.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
PSA, DRE, and clinical history primarily determine need for prostate biopsy:
  • In general, total PSA ≥4 ng/mL concerning for CaP (sensitivity 21%, specificity 91%)
    • Other benign conditions can elevate PSA (infection, inflammation, normal growth, natural PSA fluctuations, normally high variants)
    • Rectal manipulation will not elevate PSA.
  • Age-/race-adjusted “normal” PSA values (ng/mL):

    Age

    Asians

    Blacks

    Whites

    40-49

    0-2.0

    0-2.0

    0-2.5

    50-59

    0-3.0

    0-4.0

    0-3.5

    60-69

    0-4.0

    0-4.5

    0-4.5

    70-79

    0-5.0

    0-5.5

    0-6.5

  • 5-&agr;-Reductase inhibitors decrease PSA by ˜50%.
  • Other PSA metrics used to aid in CaP diagnosis: PSA velocity, PSA doubling time, PSA density, percentage free PSA
    • Total PSA velocity: ≥0.75 ng/mL/year or >20% baseline for higher values increases CaP risk
    • Free PSA and age/race-adjusted PSA helpful in evaluating risk
    • PSAD (PSA density) ≥0.15 associated with higher prevalence of CaP
  • PSA/free PSA and probability of cancer:

    PSA (ng/dL)

    Cancer Rate

    % Free PSA (for PSA 4-10)

    Cancer Rate

    0-2

    1%

    0-10%

    56%

    2-4

    15%

    10-15%

    28%

    4-10

    25%

    15-20%

    20%

    >10

    >50%

    20-25%

    16%

    >25%

    8%

  • Prostate biopsy
    • Decision to biopsy involves PSA, DRE findings, and overall clinical suspicion of CaP.
    • Standard biopsy includes systematic random cores from the peripheral zone-base, mid, and apex, generally 8 to 12 cores.
    • The Gleason Grade is the standard pathologic grading system:
      • Ranks specimens from 1 to 5 based on architectural pattern identified, with 1 being most differentiated and 5 being least.
      • Primary and secondary patterns are identified and reported, and the sum is the Gleason score (e.g., 3 + 4 = 7).
      • Most prostate cancer is scored 6 to 10 with 10 having the worst prognosis.
  • Staging
    • TNM (tumor, node, and metastasis) staging is used to generate a clinical and pathological stage, which primarily directs treatment. Clinical staging is as follows:
      • T1: cancer found incidentally on TURP or found on biopsy for elevated PSA
      • T2: cancer found on DRE but confined to the prostate
      • T3: cancer found to be extended locally outside of the prostate and/or the seminal vesicle
      • T4: invading adjacent organs
      • N1: denotes local lymph node spread
      • M1: distant metastasis
Follow-Up Tests & Special Considerations
  • Bone scan and/or CT scan and/or MRI may be indicated for high-risk cancers.
  • Biopsy if suspicious nodal findings
  • Alkaline phosphatase associated with bony mets
  • Genetic testing (e.g., Prolaris, Oncotype Dx, etc.) is emerging as a prognostic modality.
image TREATMENT
Treatment options include:
  • Watchful waiting: monitoring with expectation to provide palliation with symptoms
  • Active surveillance: close monitoring of PSA, DRE, and repeat biopsy at regular intervals (3)
  • Radical prostatectomy: ± pelvic lymph node dissection (PLND)
  • Radiation therapy: external beam (EBRT)
  • Brachytherapy: radioactive implants placed in prostate; option for early clinical stage localized to the prostate
  • Androgen deprivation therapy (ADT) may be surgical or nonsurgical:
    • Bilateral orchiectomy (surgical castration)
    • Gonadotropin-releasing hormone (GnRH) agonist, antagonist, or antiandrogen (medical castration)
  • Chemotherapy: includes multiple chemotherapeutic agents used to treat castrate resistant prostate cancer
P.855

RISK STRATIFICATION
  • Treatment options based upon risk: low, intermediate, and high-risk categories; this is based on risk of recurrence after definitive treatment. Must meet all three criteria to be low risk; any one criterion moves patient to a higher risk group (4)[A]:

    Risk Category

    Clinical Stage

    Serum PSA

    Gleason Score

    Low

    T1-T2a

    <10 ng/mL

    ≤6

    Intermediate

    T2b-T2c

    >10 and ≤20 ng/mL

    7

    High

    T3a

    >20 ng/mL

    8-10

  • Localized CaP
    • Low risk:
      • Mainstay of therapy is active surveillance.
      • Radical prostatectomy and radiation therapy may be offered.
    • Intermediate risk:
      • Mainstay of therapy is radical prostatectomy with LND or radiation therapy.
      • Radical prostatectomy has shown a survival benefit in intermediate and high risk prostate cancer (5)[A]
    • High Risk:
      • Mainstay of therapy is radical prostatectomy or radiation therapy.
      • Adjuvant radiation may be considered based on adverse pathologic findings after prostatectomy
  • Locally advanced CaP:
    • Mainstay of therapy is ADT and radiation. Surgery and adjuvant radiation may also play a role.
  • Metastatic CaP:
    • Mainstay of therapy is RT and ADT.
    • ADT specifics:
      • GnRH agonists include leuprolide or goserelin.
      • GnRH antagonists include degarelix: an alternative to GnRH agonists; suppresses testosterone production and avoids flare phenomenon observed with GnRH agonists
      • Side effects of ADT: osteoporosis, gynecomastia, erectile dysfunction (ED), decreased libido, obesity, lipid alterations, greater risk of diabetes, and cardiovascular disease
      • Flare phenomenon (disease flare: hot flashes, fatigue) can occur owing to transient increase in testosterone levels on initiation of GnRH agonist therapy.
      • If spinal cord metastases are present, the concern for cord compression with a testosterone flare can be avoided by starting antiandrogen therapy prior to initiation of a GnRH agonist.
      • Combined androgen blockade with GnRH agonist and antiandrogen (e.g., bicalutamide, nilutamide, or flutamide) may be used to prevent flare.
  • Castration-resistant prostate cancer (CRPC)
    • CRPC is defined as progression of disease following ADT. Treatment includes the following:
      • Nonmetastatic
        • Continue ADT, no further treatment has been shown to increase overall survival.
        • Antiandrogen or androgren synthesis inhibitor (e.g., ketoconazole) may be added.
      • Asymptomatic metastatic: no previous therapy with docetaxel:
        • Abiraterone: inhibitor of CYP17A (adrenal androgen production), used with prednisone
        • Enzalutamide: androgen receptor inhibitor
        • Docetaxel: chemotherapeutic that inhibits microtubules
        • Sipuleucel-T: immunotherapy
      • Symptomatic metastatic: no previous therapy with docetaxel:
        • Abiraterone, enzalutamide, docetaxel
        • Radium-223 (radiopharmaceutical) for patients with symptomatic bony metastases and no visceral metastasis.
      • Symptomatic metastatic: previous therapy with docetaxel:
        • Good performance status: abiraterone, enzalutamide, cabazitaxel
        • Poor performance status: Mainstay is palliative care, may attempt further therapy based on patient wishes.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Prostatectomy: PSA and DRE are recommended at regular intervals. PSA threshold defining biochemical recurrence is evolving; however, recent data suggests a cutoff of 0.2 ng/mL (4). A CT and bone scan are usually obtained. If the PSA recurrence is thought to be from local disease, salvage radiation is considered. For metastatic disease, androgen deprivation is considered.
  • XRT: PSA and DRE are recommended at regular intervals. Biochemical recurrence is defined as PSA increase ≥2 ng/mL above nadir, a CT and bone scan are usually obtained. If the PSA recurrence is thought to be from local disease, salvage prostatectomy or cryosurgery is considered. For metastatic disease, androgen deprivation is considered.
PROGNOSIS
  • Localized disease is frequently curable; advanced disease has a favorable prognosis if lesions are hormone-sensitive.
  • 5-year CaP survival by stage: local 100%, regional 100%, distant 28%
  • Recurrence risk increased if adverse pathologic features are present: extraprostatic extension, seminal vesicle invasion, positive surgical margins
REFERENCES
1. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215-224.
2. Moyer VA; U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134.
3. Klotz L. Active surveillance for low-risk prostate cancer. F1000 Med Rep. 2012;4:16.
4. D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969-974.
5. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203-213.
Additional Reading
&NA;
  • Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26(2):242-245.
  • Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380(9858):2018-2027.
  • Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-1556.
  • Lowrance WT, Scardino PT. Predictive models for newly diagnosed prostate cancer patients. Rev Urol. 2009;11(3):117-126.
  • National Comprehensive Cancer Network. Clinical practice guidelines: prostate cancer. 2015. www.nccn.org. Accessed 2015.
  • Nomiya T, Tsuji H, Toyama S, et al. Management of high-risk prostate cancer: radiation therapy and hormonal therapy. Cancer Treat Rev. 2013;39(8): 872-878.
  • Pastuszak AW, Pearlman AM, Lai WS, et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol. 2013;190(2):639-644.
  • Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384(9959):2027-2035.
  • Thompson IM Jr, Goodman PJ, Tangen CM, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med. 2013;369(7): 603-610.
Codes
&NA;
ICD10
C61 Malignant neoplasm of prostate
Clinical Pearls
&NA;
  • Prostate cancer is clinically diverse, ranging from low-risk/indolent disease to high-risk/aggressive disease.
  • Most men with CaP are asymptomatic.
  • The use of PSA for CaP screening is controversial and necessitates an open conversation between medical provider and patient regarding benefits/risks.
  • Active surveillance is an important treatment option to consider for low-risk patients.
  • In patients taking 5-&agr;-reductase inhibitors, PSA level to estimate actual PSA.